Is TIMP3 p.Ala199Pro (c.595G>C) pathogenic?

TIMP3 p.Ala199Pro (c.595G>C) is classified Uncertain significance in TIMP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-23). AlphaMissense: likely benign (0.2581); Very rare (popmax 0.0022%, sas).

How common is TIMP3 p.Ala199Pro (c.595G>C) in the general population?

TIMP3 p.Ala199Pro (c.595G>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about TIMP3 p.Ala199Pro (c.595G>C)?

AlphaMissense predicts likely benign (score 0.2581) — an in-silico prediction, not a clinical call.

TIMP3 p.Ala199Pro

c.595G>C · VCV3674462

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2581 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.2581	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -4.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 4.2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 137 bp · p 0.036 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,048 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00112% 18/1,613,114 alleles · very rare exomes 18/1,460,956 · genomes 0/152,158 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,524
European (non-Finnish)	0.00136%	73,748

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TIMP3
Protein: p.Ala199Pro
Coding: c.595G>C
MANE Select: NM_000362
Type: single nucleotide variant
Location: chr22:32859336 (GRCh38)

Full TIMP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/timp3-p-ala199pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown